The WHO has targeted malaria amongst the five most devastating diseases worldwide. Malaria accounts for over 600 million new cases and more than 2 million deaths annually. The most dangerous species of parasite causing malaria is Plasmodium falciparum. This species may cause neurovascular involvement leading to coma and death. The life cycle of this parasite is complex. It includes various parasite forms in the arthropod vector, the mosquito, as well as liver (exoerythrocytic) and blood (erythrocytic) forms of the parasite in the human host. During blood stage development the pathway proceeds from ring to trophozoite to schizont, and finally to individual merozoites which initiate the next round of infection of red blood cells. During this asexual blood stage cycle, some of the ring stage parasites differentiate into sexual forms. Male (micro) and female (macro) gametocytes are the only forms of the malaria blood stage parasite capable of resulting in infection of the mosquito, thus completing the entire life cycle. Little is known about the initiation of gametocytogenesis (switch from asexual to sexual blood stage) or gametogenesis (switch from sexual blood stage to sexual mosquito stage). Currently, it is thought that gametocytogenesis is initiated by cAMP, while gametogenesis is thought to be initiated by Ca++ and cGMP. To determine the mechanism of transcriptional control of these differentiation events, we have begun by isolating cDNA and genomic clones of the enzymes and signaling proteins which are important in producing or transporting these second messengers: adenylate cyclase, guanylate cyclase and sarcalumenin. The products of these proteins would directly effect the various signal transduction pathways in the cell. With the current ability to transfect Plasmodium falciparum parasites in vitro, we hope to use these genes to produce Gain-of-Function as well as Loss-of-Function mutants. Ultimately, understanding the regulatory events responsible for stage differentiation may provide further insight into disrupting the normal life cycle of this deadly parasite.